Proteins with expanded polyglutamine domains cause eight inherited neurodegenerative diseases, including Huntington's disease (HD). These disorders primarily effect the motor control systems and some are associated with psychiatric symptoms and/or dementia. The diseases are relentlessly progressive and ultimately lead to death, but no treatments exist. The length of the polyglutamine domain determines the age of disease onset and disease phenotype, but the molecular mechanism(s) responsible for pathogenesis are unknown. Monoclonal antibodies are available that selectively recognize polyglutamine domain proteins with expanded repeats and the expanded repeat proteins display unique protein interactions indicating that they adopt a novel conformation. The novel conformation is hypothesized to result in unique pathogenic protein interactions that cause neuronal death and aggregation, which are hallmarks of these diseases. Perturbing abnormal polyglutamine protein interactions may interfere with disease pathogenesis and, therefore, be therapeutically useful. Mechanisms of polyglutamine-protein interaction are poorly understood. In this application, polyglutamine-protein interactions will be characterized using a novel in vitro system, tissue culture, brain slices and transgenic animals. Polyglutamine-binding peptides have been identified by screening a combinatorial peptide library. These peptides inhibit aggregation in vitro and in cells will be used to determine the sequence requirements for binding to an expanded polyglutamine domain and to optimize inhibition of interaction. The effect of optimized polyglutamine-binding peptides on aggregation and cell death will be studied in model systems such as transfected cells and transfected brain slices. Polyglutamine-binding peptide expressing transgenic mice will be generated and mated to polyglutamine disease expressing mice to determine the effect on symptom development and pathogenesis.